This invention relates to new pyridine compounds. More particularly, this invention relates to new pyridine compounds and pharmaceutically acceptable salts thereof which have pharmacological activities, a process for preparation thereof, a pharmaceutical composition comprising the same and a use of the same.
Accordingly, one object of this invention is to provide the new and useful pyridine compounds and pharmaceutically acceptable salts thereof which possess a strong inhibitory activity on the production of nitric oxide (NO).
Another object of this invention is to provide a process for the preparation of the pyridine compounds and salts thereof.
A further object of this invention is to provide a pharmaceutical composition comprising said pyridine compound or a pharmaceutically acceptable salt thereof.
Still further object of this invention is to provide a use of said pyridine compounds or pharmaceutically acceptable salts thereof as a medicament for prophylactic and therapeutic treatment of nitric oxide synthase (NOS)-mediated diseases such as adult respiratory distress syndrome, myocarditis, synovitis, septic shock, insulin-dependent diabetes mellitus, ulcerative colitis, cerebral infarction, rheumatoid arthritis, osteoarthritis, osteoporosis, systemic lupus erythematosus, rejection by organ transplantation, asthma, pain, ulcer, and the like in human being and animals.
The object pyridine compounds of the present invention are novel and can be represented by the following general formula (I) 
wherein
R1 and R2 are the same or different and each is hydrogen, lower alkyl, lower alkoxy, cyano, lower alkoxycarbonyl, carboxy, lower haloalkyl, hydroxy(lower)alkyl, hydroxy, nitro, amino, mono or di(lower)alkylamino, protected hydroxy or lower alkyl substituted by protected hydroxy;
X is a single bond or a group of the formula selected from the group consisting of 
wherein R4 is hydrogen or acyl;
ring A is heterocycle or arylene wherein said heterocycle and arylene may be substituted by suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, halogen and guanidino which may be substituted by suitable substituent(s); and
R3 is a group of the formula selected from the group consisting of 
wherein R5 is hydrogen, lower alkyl, lower alkylthio, amino which may be substituted by suitable substituent(s) or aromatic heterocyclic group, or when 
xe2x80x83may form a bicyclic group selected from the group consisting of 
xe2x80x83wherein said bicyclic group may be substituted by suitable substituent(s) selected from the group consisting of lower alkyl and aryl,
R6 and R7 are the same or different and each is hydrogen, lower alkyl, cyano, amino, hydroxy, acyl or amidino which may be substituted by suitable substituent(s), and R8 is thiazolinyl or pyridyl.
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include, for example, a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkaline metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,Nxe2x80x2-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); and a salt with a basic or acidic amino acid (e.g., arginine salt, aspartic acid salt, gultamic acid salt, etc.).
In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows.
The term xe2x80x9clowerxe2x80x9d is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise provided.
Suitable xe2x80x9clower alkylxe2x80x9d and xe2x80x9clower alkyl moietyxe2x80x9d in the terms xe2x80x9chydroxy(lower)alkylxe2x80x9d, xe2x80x9cmono or di(lower)alkylaminoxe2x80x9d and xe2x80x9clower alkylthioxe2x80x9d include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, tert-pentyl and hexyl, in which more preferred one is C1-C4 alkyl.
Suitable xe2x80x9clower alkoxyxe2x80x9d and xe2x80x9clower alkoxy moietyxe2x80x9d in the term xe2x80x9clower alkoxycarbonylxe2x80x9d include, straight or branched one having 1 to 6 carbon atom(s), such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, neopentyloxy, tert-pentyloxy and hexyloxy, in which more preferred one is C1-C4 alkoxy.
Suitable xe2x80x9clower alkoxycarbonylxe2x80x9d includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl.
Suitable xe2x80x9clower haloalkylxe2x80x9d includes, straight or branched one having 1 to 6 carbon atom(s), such as trifluoromethyl, trichloromethyl and tribromomethyl, in which more preferred one is trifluoromethyl.
Suitable xe2x80x9chydroxy(lower)alkylxe2x80x9d includes, for example, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 2-hydroxy-1-methylethyl, 4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl, 1-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5-hydroxypentyl and 6-hydroxyhexyl.
Suitable xe2x80x9cmono or di(lower)alkylaminoxe2x80x9d includes, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, N, N-dimethylamino, N, N-diethylamino, N,N-dipropylamino, N,N-dibutylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino and N-butyl-N-methylamino.
Suitable xe2x80x9cacylxe2x80x9d includes, for example, carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or a heterocyclic ring, which is referred to as heterocyclic acyl.
Suitable examples of said acyl are illustrated as follows: carbamoyl; aliphatic acyl such as lower alkanoyl which may be substituted by one to three halogen atoms (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, trichloroacetyl, trifluoroacetyl, etc.), lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxycarbonyl, etc.), lower alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.), lower alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl, etc.), cyclo(lower)alkylcarbonyl (e.g., cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), and the like; aromatic acyl such as aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.), aryl(lower)alkanoyl [e.g., phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, etc.), naphthyl(lower)alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.], aryl(lower)alkoxycarbonyl [e.g., phenyl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), etc.], aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.), aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.), arylsulfonyl (e.g., phenylsulfonyl, p-tolylsufonyl, etc.), and the like; heterocyclic acyl such as indolylcarbonyl (e.g., indolyl-2-ylcarbonyl, etc.), benzofuranylcarbonyl (e.g., benzofuran-2-ylcarbonyl), quinoxalinylcarbonyl, quinolylcarbonyl, pyrrolylcarbonyl, benzimidazolylcarbonyl, benzothienylcarbonyl, benzothiazolylcarbonyl, imidazolylcarbonyl, pyridylcarbonyl, morpholinylcarbonyl (e.g., morpholinocarbonyl) and the like. More preferred examples of xe2x80x9cacylxe2x80x9d include lower alkanoyl having 1 to 6 carbon atoms (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, etc.) and lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxycarbonyl, etc.).
Suitable examples of xe2x80x9chydroxy protective groupxe2x80x9d include aforesaid acyl (e.g., acetyl, trichloroacetyl, etc.), mono(or di or tri)phenyl(lower)alkyl which may have one or more suitable substituent(s) (e.g., benzyl, 4-methoxybenzyl, trityl, etc.), trisubstituted silyl [e.g., tri(lower)alkylsilyl (e.g., trimethylsilyl, tert-butyldimethylsilyl, etc.), etc.], tetrahydropyranyl and the like.
Suitable examples of xe2x80x9cprotected hydroxyxe2x80x9d include tri(lower)-alkylsilyloxy (e.g., trimethylsilyloxy, tert-butyldimethylsilyloxy, etc.), acyloxy (e.g., acetoxy, etc.), mono(or di or tri)phenyl(lower)alkyloxy (e.g., benzyloxy, etc.) and tetrahydropyranyloxy.
Suitable examples of xe2x80x9clower alkyl substituted by protected hydroxyxe2x80x9d include tri(lower)alkylsilyloxy(lower)alkyl (e.g., trimethylsilyloxymethyl, tert-butyldimethylsilyloxymethyl, 2-(trimethylsilyloxy)ethyl, 2-(tert-butyldimethylsilyloxy)ethyl, etc.), acyloxy(lower)alkyl (e.g., acetoxymethyl, etc.), mono(or di or tri)phenyl(lower)alkyloxy(lower)alkyl (e.g., benzyloxymethyl, etc.) and tetrahydropyranyloxy(lower)alkyl (e.g., tetrahydropyranyloxymethyl, etc.).
Suitable xe2x80x9cheterocyclexe2x80x9d for ring A includes heterocycle containing nitrogen atom(s) and heterocycle containing nitrogen atom(s) and sulfur atom(s). Suitable xe2x80x9cheterocycle containing nitrogen atom(s)xe2x80x9d includes saturated or unsaturated 5 or 6-membered heteromonocycle containing 1 to 4 nitrogen atom(s), for example, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, pyridine, dihydropyridine, pyrimidine, pyrazine, pyridazine, triazole, tetrazole, triazine, pyrrolidine, imidazolidine, pyrazolidine, piperidine and piperazine, in which more preferred ones are pyrimidine, imidazole and pyrrolidine. Suitable xe2x80x9cheterocycle containing nitrogen atom(s) and sulfur atom(s)xe2x80x9d includes saturated or unsaturated 5 or 6-membered heteromonocycle containing I to 3 nitrogen atom(s) and 1 or 2 sulfur atom(s), for example, thiazole, isothiazole, thiadiazole, thiazine, dihydrothiazine and thiazolidine, in which more preferred one is thiazole.
Suitable xe2x80x9carylenexe2x80x9d for ring A includes phenylene (e.g., 1,2-phenylene, 1,3-phenylene, 1,4-phenylene) and naphthylene (e.g., 1,2-naphthylene, 1,3-naphthylene, 1,4-naphthylene, 1,5-naphthylene, 1,6-naphthylene, 1,7-naphthylene, 1,8-naphthylene, 2,3-naphthylene, 2,6-naphthylene, 2,7-naphthylene), in which more preferred one is phenylene.
Suitable examples of ring A include those represented by the following formulas: 
Suitable xe2x80x9chalogenxe2x80x9d includes, for example, fluorine, bromine, chlorine and iodine.
xe2x80x9cGuanidino which may be substituted by suitable substituent(s)xe2x80x9d includes a group of the formula 
wherein R9 and R1 are the same or different and each is hydrogen, lower alkyl, cyano or amino protective group. Suitable examples of said amino protective group include lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxycarbonyl, etc.).
Suitable xe2x80x9clower alkylthioxe2x80x9d includes, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, neopentylthio, tert-pentylthio and hexylthio, in which more preferred one is C1-C4 alkylthio.
Suitable substituent(s) in the term xe2x80x9camino which may be substituted by suitable substituent(s)xe2x80x9d includes lower alkyl, acyl (e.g., lower alkoxycarbonyl) and cyano.
Suitable examples of xe2x80x9camino which may be substituted by suitable substituent(s)xe2x80x9d include amino, mono or di(lower)alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino, N,N-dibutylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-butyl-N-methylamino, etc.), acylamino [e.g., lower alkoxycarbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, tert-butoxycarbonylamino, tert-pentyloxycarbonylamino, etc.)] and cyanoamino.
Suitable xe2x80x9caromatic heterocyclic groupxe2x80x9d includes 5 or 6-membered aromatic heteromonocyclic group containing at least one hetero atom selected from sulfur atom, oxygen atom and nitrogen atom, for example, thienyl, furyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. Preferred one is 5-membered aromatic heteromonocyclic group containing sulfur atom or oxygen atom, for example, thienyl (e.g., 2-thienyl, 3-thienyl) and furyl (e.g., 2-furyl, 3-furyl), in which more preferred one is thienyl (e.g., 2-thienyl, 3-thienyl).
Suitable xe2x80x9carylxe2x80x9d includes, for example, phenyl and naphthyl, in which more preferred one is phenyl.
xe2x80x9cAmidino which may be substituted by suitable substituent(s)xe2x80x9d includes a group of the formula 
wherein R11 and R12 are the same or different and each is hydrogen, lower alkyl, cyano or amino protective group. Suitable examples of said amino protective group include lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxycarbonyl, etc.).
Suitable xe2x80x9cthiazolinylxe2x80x9d includes, for example, 2-thiazolinyl.
Suitable xe2x80x9cpyridylxe2x80x9d includes, for example, 2-pyridyl, 3-pyridyl and 4-pyridyl.
Suitable xe2x80x9camino protective groupxe2x80x9d includes, for example, acyl (e.g., lower alkoxycarbonyl, aryl(lower)alkoxycarbonyl, etc.) and conventional protective group such as mono(or di or tri)aryl(lower)alkyl, for example, mono(or di or tri)phenyl(lower)alkyl (e.g., benzyl, benzhydryl, trityl, etc.), in which more preferred one is lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxycarbonyl, etc.).
According to the present invention, the object compound (I) can be prepared by the following processes. 
wherein
R1, R2, R3, R5, R6, R7, R8, X and ring A are each as defined above,
R13 is acyl,
R14 is hydrogen or lower alkyl,
Z1, Z2 and Z3 are each halogen,
R16, R17, R18, R19, R20, R21, R22 and R2 are each lower alkyl,
R4a is acyl,
R15 and R26 are each amino protective group,
R23 is lower alkyl or aromatic heterocyclic group,
R25 is hydrogen or lower alkyl
R27 is lower alkyl or aryl, and
X1 is sulfur atom or oxygen atom.
The starting compounds or a salt thereof can be prepared by the procedures described in the Preparations mentioned below or by a process known in the art for preparing their structually analogous compounds.
The processes for preparing the object compound (I) of the present invention are explained in detail in the following.
Process (1)
The compound (I-1) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III) in the presence of 1-methyl-2-chloropyridinium iodide and an organic base such as tri(lower)alkylamine (e.g., diisopropylethylamine).
The reaction is usually carried out in a conventional solvent such as alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvents which do not adversely affect the reaction, or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
Process (2)
The compound (I-3) or a salt thereof can be prepared by subjecting the compound (I-2) or a salt thereof to deacylation.
Suitable method of this deacylation includes conventional one such as hydrolysis, reduction and the like. The hydrolysis is preferably carried out in the presence of a base or an acid.
Suitable base includes an inorganic base and an organic base such as an alkali metal [e.g., sodium, potassium, etc.], an alkaline earth metal [e.g., magnesium, calcium, etc.], the hydroxide or carbonate or hydrogencarbonate thereof, trialkylamine [e.g., trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-one, or the like.
Suitable acid includes an organic acid [e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.], and an inorganic acid [e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.].
The reaction may be carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvents which do not adversely affect the reaction, or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
Process (3)
The compound (I-4) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V).
The reaction is usually carried out in a conventional solvent such as ethyl acetate, methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.) or any other organic solvents which do not adversely affect the reaction, or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
Process (4)
The compound (1-10) or a salt thereof can be prepared by subjecting the compound (I-9) or a salt thereof to reduction.
This reaction can be carried out in a similar manner to the reaction in the aforementioned Process (3), and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (3).
Process (5)
The compound (I-11) or a salt thereof can be prepared by reacting the compound (I-10) or a salt thereof with triethylsilane (XII).
The reaction is usually carried out in a conventional solvent such as ethyl acetate, methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.) or any other organic solvents which do not adversely affect the reaction, or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
Process (6)
The compound (I-12) or a salt thereof can be prepared by reacting the compound (I-10) or a salt thereof with acetonitrile and sulfuric acid.
This reaction can be carried out in a similar manner to the reaction in the aforementioned Process (5), and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (5).
Process (7)
The compound (X) or a salt thereof can be prepared by reacting the compound (VIII) or a salt thereof with the compound (IX).
This reaction can be carried out in the same manner as in Preparation 15 or in a similar manner thereto.
Process (8)
The compound (I-8) or a salt thereof can be prepared by reacting the compound (X) or a salt thereof with the compound (XI).
This reaction can be carried out in the same manner as in Example 23 or in a similar manner thereto.
Process (9)
The compound (I-10) or a salt thereof can be prepared by subjecting the compound (1-9) or a salt thereof to reduction.
This reaction can be carried out in the same manner as in Example 24 or in a similar manner thereto.
Process (10)
The compound (I-11) or a salt thereof can be prepared by reacting the compound (1-10) or a salt thereof with triethylsilane (XII).
This reaction can be carried out in the same manner as in Example 25 or in a similar manner thereto.
Process (11)
The compound (I-12) or a salt thereof can be prepared by reacting the compound (1-10) or a salt thereof with acetonitrile and sulfuric acid.
This reaction can be carried out in the same manner as in Example 26 or in a similar manner thereto.
Process (12)
The compound (I-13) or a salt thereof can be prepared by subjecting the compound (I-12) or a salt thereof to deacetylation.
This reaction can be carried out in a similar manner to the reaction in the aforementioned Process (2), and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process (2).
Process (13)
The compound (I-14) or a salt thereof can be prepared by subjecting the compound (I-13) or a salt thereof to acylation.
Suitable examples of an acylating agent to be used in the acylation include an acid halide (e.g. acid chloride, etc.), an acid anhydride, an activated amide and an acivated ester.
The reaction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene dichloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, pyridine, acetic acid or any other organic solvents which do not adversely affect the reaction, or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
The reaction may be carried out in the presence of an inorganic or organic base such as an alkali metal hydrogencarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine and N,N-di(lower)alkylbenzylamine.
Process (14)
The compound (I-15) or a salt thereof can be prepared by reacting the compound (XIII) or a salt thereof with the compound (XIV) in the presence of a reducing agent.
This reaction can be carried out in the same manner as in Example 28 or in a similar manner thereto.
Process (15)
The compound (I-16) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (XV).
This reaction can be carried out in the same manner as in Preparation 14 or in a similar manner thereto.
Process (16)
The compound (I-17) or a salt thereof can be prepared by subjecting the compound (I-16) or a salt thereof to elimination of the amino protective group.
This reaction can be carried out in the same manner as in Example 10 or in a similar manner thereto.
Process (17)
The compound (I-18) or a salt thereof can be prepared by reacting the compound (I-17) or a salt thereof with the compound (XVI).
This reaction can be carried out in the same manner as in Example 11 or in a similar manner thereto.
Process (18)
The compound (I-19) or a salt thereof can be prepared by reacting the compound (I-18) or a salt thereof with hydrazine.
This reaction can be carried out in the same manner as in Example 12 or in a similar manner thereto.
Process (19)
The compound (I-20) or a salt thereof can be prepared by reacting the compound (I-18) or a salt thereof with hydroxylamine.
This reaction can be carried out in the same manner as in Example 13 or in a similar manner thereto.
Process (20)
The compound (I-21) or a salt thereof can be prepared by reacting the compound (I-18) or a salt thereof with the compound (XVII).
This reaction can be carried out in the same manner as in Example 14 or in a similar manner thereto.
Process (21)
The compound (I-22) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (XVIII).
This reaction can be carried out in the same manner as in Example 16 or in a similar manner thereto.
Process (22)
The compound (I-23) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (XIX).
This reaction can be carried out in the same manner as in Example 17 or in a similar manner thereto.
Process (23)
The compound (I-24) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (XX).
This reaction can be carried out in the same manner as in Example 19 or in a similar manner thereto.
Process (24)
The compound (I-25) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (XXI).
This reaction can be carried out in the same manner as in Example 20 or in a similar manner thereto.
Process (25)
The compound (I-26) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (XXII).
This reaction can be carried out in the same manner as in Example 21 or Example 69 or in a similar manner thereto.
Process (26)
The compound (I-27) or a salt thereof can be prepared by subjecting the compound (XXIII) or a salt thereof to ring-closing reaction in the presence of a reducing agent.
This reaction can be carried out in the same manner as in Example 96 or Example 97 or in a similar manner thereto.
Process (27)
The compound (I-28) or a salt thereof can be prepared by reacting the compound (XXIV) or a salt thereof with the compound (XXV).
This reaction can be carried out in the same manner as in Example 98 or in a similar manner thereto.
Process (28)
The compound (I-29) or a salt thereof can be prepared by subjecting the compound (XXVI) or a salt thereof to elimination of the protective groups.
This reaction can be carried out in the same manner as in Example 100 or in a similar manner thereto.
Process (29)
The compound (I-30) or a salt thereof can be prepared by reacting the compound (XXVII) or a salt thereof with cyanogen bromide.
This reaction can be carried out in the same manner as in Example 102 or in a similar manner thereto.
Process (30)
The compound (I-31) or a salt thereof can be prepared by reacting the compound (XXVIII) or a salt thereof with cyanogen bromide.
This reaction can be carried out in the same manner as in Example 103 or in a similar manner thereto.
Process (31)
The compound (I-32) or a salt thereof can be prepared by subjecting the compound (XXIX) or a salt thereof to reduction.
This reaction can be carried out in the same manner as in Example 106 or in a similar manner thereto.
Process (32)
The compound (I-33) or a salt thereof can be prepared by reacting the compound (XXX) or a salt thereof with sodium hydride.
This reaction can be carried out in the same manner as in Example 107 or in a similar manner thereto.
The compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like.
It is to be noted that the compound (I) and the other compounds may include one or more stereoisomer(s) such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s), and all of such isomers and mixtures thereof are included within the scope of this invention.
Furthermore, with regard to the compound (I), it is to be noted that the following formula (A) is well known to be a tautomeric isomer of the following formula (B), and accordingly, it is to be understood that both of the isomers are substantially the same. 
wherein R5, R6 and R7 are each as defined above, and R is hydrogen or a substituent such as lower alkyl, acyl or cyano.
Accordingly, the both of the tautomeric forms are clearly included within the scope of the present invention. In the present specification, the object and starting compounds including the group of such tautomeric isomers are represented by using one of the expressions.
The object compounds (I) and pharmaceutically acceptable salts thereof include solvates [e.g., enclosure compounds (e.g., hydrate, etc.)].
The object compounds (I) and pharmaceutically acceptable salts thereof possess a strong inhibitory activity on the production of nitric oxide (NO).
Accordingly, the object compounds (I) and pharmaceutically acceptable salts thereof are expected to possess a nitric oxide synthase (NOS)-inhibitory activity or a NOS-production inhibitory activity.
Accordingly, they are useful for prevention and/or treatment of NOS-mediated diseases such as adult respiratory distress syndrome, myocarditis, synovitis, septic shock, insulin-dependent diabetes mellitus, ulcerative colitis, cerebral infarction, rheumatoid arthritis, osteoarthritis, osteoporosis, systemic lupus erythematosus, rejection by organ transplantation, asthma, pain, ulcer, and the like in human being or animals.
In order to illustrate the usefulness of the object compound (I), the pharmacological test data of the representative compound of the compound (I) are shown in the following.
Test: Binding Assay Using Nitric Oxide Synthase (NOS)
(1) Test method
A crude preparation of NOS was obtained from brains of male SD rats. The whole brain (including cerebellum) was homogenized with 5 volume (W/V) of 50 mM Tris buffer (pH 7.0 at 4xc2x0 C.) and centrifuged at 48,000xc3x97g for 20 minutes. The pellet was discarded and the supernatant was passed through xc2xc volume (V/V) of Dowex AG50WX-8 resin (Na+ form), in order to remove endogenous arginine. The supernatant was collected, the pH was adjusted to 7.0 at 22xc2x0 C., and this cytosolic preparation was frozen and stored at xe2x88x9280xc2x0 C. until required. In the binding assay, each drug was incubated with the brain cytosol (200 xcexcg protein/tube) in 0.15 ml (final volume) of 50 mM Tris buffer containing 10 xcexcM CaCl2 and 10 nM [3H]Na (Amersham, UK). Incubation was performed at 27xc2x0 C. for 90 minutes and terminated by vacuum filtration through 0.3% polyethyleneimine pretreated GF/B glass fibre filters which were subsequently washed with distilled water (4xc2x0 C., 4 mlxc3x974). Nonspecific binding was defined by use of 100 xcexcl Na. Data are expressed as inhibition % of specific binding.
(2) Test Compounds
(a) 2-Guanidino-4-methyl-5-(4-methoxypyridin-2-yl)thiazole
(b) (5-(4-Methoxypyridin-2-yl)-2-methylphenyl)guanidine dihydrochloride
(c) N-(3-(4-Methoxypyridin-2-yl)phenyl)-S-ethylisothiourea dihydrochloride
(d) 2-Amino-7-(4-methoxypyridin-2-yl)quinoline dihydrochloride
(e) 2-Amino-7-(4-methylpyridin-2-yl)quinoline dihydrochloride
(f) 7-(4-Methoxypyridin-2-yl)-2-methylaminoquinoline dihydrochloride
Test Result
For therapeutic administration, the object compound (I) of the present invention and pharmaceutically acceptable salts thereof are used in the form of a conventional pharmaceutical preparation in admixture with a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration. The pharmaceutical preparation may be compounded in a solid form such as granule, capsule, tablet, dragee or suppository, or in a liquid form such as solution, suspension or emulsion for injection, ingestion, eye drop, etc. If needed, there may be included in the above preparation auxiliary substance such as stabilizing agent, wetting or emulsifying agent, buffer or any other commonly used additives.
The optimal dosage of effective ingredient which may be usually selected from the range of 0.001 mg/kg to 50 mg/kg, preferably 0.01 mg/kg to 10 mg/kg, is administered 1 to 4 times a day. However, the above dosage may be increased or decreased according to age, body weight and conditions of the patient or administering method.
The preferred embodiments of the pyridine compounds of the present invention represented by the general formula (I) are as follows.
1) The compound of the formula (I) wherein
R1 and R2 are the same or different and each is hydrogen, lower alkyl, lower alkoxy, cyano, lower alkoxycarbonyl, carboxy, lower haloalkyl, hydroxy(lower)alkyl, hydroxy, nitro, amino or mono or di(lower)alkylamino.
2) The compound of the formula (I) wherein
ring A is a ring selected from the group consisting of 
xe2x80x83wherein said ring A may be substituted by suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, halogen and guanidino.
3) The compound of the formula (I) wherein R3 is 
wherein R5, R6 and R7 are as defined above.
4) The compound of the formula (I) wherein R3 is 
wherein R5 is hydrogen, lower alkyl, lower alkylthio, amino, mono or di(lower)alkylamino, acylamino, cyanoamino or 5-membered aromatic heteromonocyclic group containing sulfur atom or oxygen atom, or 
xe2x80x83may form a bicyclic group selected from the group consisting of 
xe2x80x83wherein said bicyclic group may be substituted by suitable substituent(s) selected from the group consisting of lower alkyl and aryl, and
R6 and R7 are the same or different and each is hydrogen, lower alkyl, cyano, amino, hydroxy or amidino which may be substituted by suitable substituent(s) selected from the group consisting of lower alkyl and cyano.